Metanalyses, Metapsychoses

Type 2 diabetes mellitus and cardiovascular disease share common antecedents ("insulin resistance syndrome") which include vasoactive cytokines. Poor glycemic control in Type 2 diabetes associates very strongly with macrovascular disease. Nevertheless, improving glycemia long-term does not reduce macrovascular mortality.

Impaired glucose tolerance - which is characterized by relative normoglycemia – associates by itself significantly with macrovascular disease which in turn associates strongly with increased levels of inflammatory vasoactive cytokines. Hyperglycemia - relentlessly progressive in type 2 diabetes - further associates quite powerfully with increased levels of inflammatory vasoactive cytokines.

Agents which have been shown to causally diminish atherosclerotic events have also been seen to favorably impact glycemic control. Ramipril, an ACE inhibitor (in HOPE) , as well as pravastatin, an HMG-CoA reductase inhibitor (in WESCOPS) may actually not only improve glycemia but also delay progression to type 2 diabetes. Coumadin – a systemic anticoagulant - may also improve glycemic control (from observational data.)

Over the long-term, therefore, it would appear much more likely that it is the macrovascular disease process itself which drives hyperglycemia by increasing vasoactive cytokines which may (1) further exacerbate insulin resistance in the face of beta-cell exhaustion and/or (2) further diminish insulin secretion.

Data from the Mayo Clinic suggests sulfonylureas are associated with enhanced cardiovascular mortality following angioplasty procedures. In settings of randomized, controlled, clinical trials, low, fixed-doses of sulfonylureas seem to improve or not change mortality measures whereas high, fixed of sulfonylureas increase cardiovascular mortality.

Initial randomization to very low-hypoglycemic potential  metformin monotherapy significantly improved cardiovascular mortality in the UKPDS. Initial randomization to very high-hypoglycemic potential metformin + sulfonylurea combination therapy significantly increased cardiovascular mortality in the same UKPDS.

US clinical trials submitted to FDA for metformin initial regulatory approval showed significantly increased mortality of patients randomized to metformin on combination metformin plus sulfonylureas. [Hypoglycemia was suggested to have played a potentially causal role].

Observational data from Malmo show increased mortality in diabetic patients taking combination metformin plus sulfonylureas. Data from the Bezafibrate Infarction Prevention Trial show an increased cardiovascular mortality from patients on combination metformin plus sulfonylureas.

Data from the US ACCORD Study have shown that long-term pharmacologic interventions to very tightly control Type 2 diabetes not only are ineffective in reducing mortality, but may contribute to increased morbidity and mortality. 

Data from the UGDP, the UKPDS, ACCORD, ADVANCE, and VA-Diabetes Trial have all failed to show any macrovascular, let alone  mortality, benefit of tighter glucose control.

Nevertheless, regrettably, but understandably, there are those for whom the old hypothesis outweighs the overwhelming preponderance of data, and data dredging nonsense like this one reported in Diabetologia persist.

-Current ADA Treatment Guidelines for Type 2 glycemic control of target A1c at 7% and action point at 8% should be maintained and not tightened.

-Companies developing weight-loss strategies for diabetes like Amylin, Eli Lilly, Sanofi-Aventis, Novo Nordisk should likely profit. Others with weight neutral or enhancing strategies like Merck or AstroZeneca or Mannkind may suffer.